CN112245400B

CN112245400B - Efavirenz micro-tablet, preparation method and application thereof

Info

Publication number: CN112245400B
Application number: CN202011248743.2A
Authority: CN
Inventors: 雅克·普什·阿兰; 萨尔瓦多·罗·布; 朱丹
Original assignee: Lanlong Pharmaceutical Beijing Co ltd
Current assignee: Lanlong Pharmaceutical Beijing Co ltd
Priority date: 2020-11-10
Filing date: 2020-11-10
Publication date: 2023-01-20
Anticipated expiration: 2040-11-10
Also published as: CN112245400A

Abstract

The invention provides an efavirenz micro-tablet, a preparation method and application thereof, relating to the technical field of medicines. The efavirenz micro-tablet comprises an inner phase and an outer phase, wherein the mass percent of the inner phase is 87-91.25%, and the mass percent of the outer phase is 8.75-13%; the inner phase comprises 70 to 80 percent of efavirenz, 4.5 to 10.25 percent of filling agent, 2 to 4 percent of adhesive, 1.5 to 10 percent of disintegrating agent and 1 to 4 percent of surfactant; the external phase comprises 4.75-10.5% of filling agent, 0.5-1% of lubricant and 0.25-0.5% of thickening agent. The invention has the advantages that the prior 600 mg/tablet large-dose efavirenz is adjusted and optimized into a 22.5-26.6 mg/tablet micro-tablet formulation, the efavirenz micro-tablet has high dissolution rate in unit time, can reach the peak within 6.5-7 hours after being taken, and can keep the same or even better bioavailability as the prior efavirenz.

Description

Efavirenz micro-tablet, preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to an efavirenz micro-tablet, a preparation method and application thereof.

Background

At present, the prostate cancer becomes the second most common cancer in men all over the world, and is also the common cancer in men ranked fifth in China. The incidence rate of prostate cancer in China is far lower than that of European and American countries, but because the early diagnosis rate is low, the mortality rate of prostate cancer patients in China is far higher than that of developed countries. Existing treatment modalities for prostate cancer include surgery, radiation therapy, endocrine therapy, chemotherapy, and novel endocrine therapy. With the prolonging of the treatment time of the prostate cancer, the prostate cancer cells are continuously mutated due to factors such as pressure brought by the treatment, and the like, and finally the prostate cancer enters a castration resistant stage, namely a Castration Resistant Prostate Cancer (CRPC) stage. The probability of tumor metastasis when CRPC is diagnosed in prostate cancer patients is as high as 85%, and more than 80% of CRPC patients have bone metastasis. There is currently no cure for metastatic castration resistant prostate cancer mCRPC in the clinic, and the main therapeutic objectives are to prolong the survival OS and improve the quality of life (QoL) of patients.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) targeting the reverse transcriptase (L1-RT) encoded by LINE-1 and is used in the medical community as a specific drug against the hiv virus. In earlier studies (patent number AU2013375157B 2), efavirenz used for treating prostate cancer was found to have a certain therapeutic effect, and endocrine therapy resistant prostate cancer was mainly treated by targeting androgen-independent resistance mechanism. Therefore, the efavirenz can be used as a novel mCRPC clinical treatment medicament and has good application and market prospect.

During the development process, the higher level (> 3000 ng/mL) of the efavirenz plasma drug concentration in the subject is found to be beneficial to the clinical treatment effect. However, in the population of subjects dosed on the same day, the plasma concentrations measured in the subjects showed significant inter-individual variation. The reason for this is, on the one hand, the difference in genotype of different subjects with respect to efavirenz metabolism; on the other hand, it may be associated with limited dissolution efficiency and bioavailability due to the low solubility of efavirenz. Currently, the marketed drug Sustiva of efavirenz is 600 mg/tablet, wherein the active ingredient belongs to a crystalline form, is almost insoluble in water, belongs to a BCS (biopharmaceutical System) II drug, and generally has the characteristics of low solubility and high permeability.

Therefore, if the dosage form and the formula of the efavirenz can be changed, the bioavailability of the efavirenz in a user body can be improved; for users needing to optimally adjust the administration dosage, the administration dosages of different users can be flexibly adjusted according to the real-time monitoring result of the blood concentration of the users, the individual difference of the blood concentration of the users after administration is reduced, the blood concentration of more users after administration can reach the effective range of clinical treatment, and the clinical research progress of efavirenz for treating prostate cancer is further promoted.

Disclosure of Invention

The invention aims to provide an efavirenz micro-tablet which has small single tablet dosage and high dissolution rate in unit time and can reach a peak within 6.5 to 7 hours after being taken.

The invention also aims to provide a preparation method of the efavirenz micro-tablet, which is characterized in that the single tablet dosage of the prepared efavirenz micro-tablet is small and the dissolution rate in unit time is high through a specific charging sequence.

The invention also aims to provide the application of the efavirenz micro-tablet, and the efavirenz micro-tablet can be used for preparing anti-cancer or anti-tumor medicines.

The technical problem to be solved by the application is achieved by adopting the following technical scheme.

On one hand, the embodiment of the application provides an efavirenz micro-tablet, which comprises an inner phase and an outer phase, wherein the mass percent of the inner phase is 87-91.25%, and the mass percent of the outer phase is 8.75-13%; the inner phase is mainly prepared from the following raw materials in percentage by mass: 70-80% of efavirenz, 4.5-10.25% of filler, 2-4% of adhesive, 1.5-10% of disintegrating agent and 1-4% of surfactant; the external phase is mainly prepared from the following raw materials in percentage by mass: 4.75 to 10.5 percent of filling agent, 0.5 to 1 percent of lubricant and 0.25 to 0.5 percent of thickening agent.

On the other hand, the embodiment of the application provides a preparation method of the efavirenz micro-tablet, which comprises the following steps: pre-dissolving a surfactant and part of a binding agent in water to obtain a granulating solution, sequentially adding efavirenz, a filling agent, a disintegrating agent and the rest of the binding agent in an inner phase into the granulating solution, and stirring and mixing uniformly to obtain a premixed material; granulating the premixed material, sieving and drying to obtain dry particles; and (3) premixing the dry granules and the materials except the thickening agent and the lubricant in the external phase, adding the thickening agent into the mixture, mixing the mixture, adding the lubricant into the mixture, mixing the mixture, and tabletting to obtain the efavirenz micro-tablet.

In another aspect, the present application provides a use of the aforementioned efavirenz micro-tablet.

Compared with the prior art, the embodiment of the application has at least the following advantages or beneficial effects:

according to the efavirenz micro-tablet provided by the invention, the filler, the disintegrant, the adhesive, the thickener and the lubricant with specific types and specific doses are added, the characteristic of low solubility of the original efavirenz is changed, and meanwhile, the prepared efavirenz micro-tablet basically reaches more than 70% within 20min, 85% or even more than 90% within 40min and is high in dissolution rate within unit time in an in vitro dissolution rate test by combining a specific granulation and tabletting process; meanwhile, after the efavirenz micro-tablet is taken, the plasma drug concentration can reach the peak within 6.5-7 hours, the bioavailability which is the same as or better than that of the original efavirenz can be kept, the administration dosage can be flexibly adjusted in the clinical research process, the difference between subjects with blood drug concentration after administration is reduced, and certain assistance is provided for promoting clinical research. In addition, in the actual use process, the dosage of the efavirenz can be flexibly adjusted according to actual needs and the bioavailability of a patient can be improved no matter the efavirenz is used for treating prostate cancer or AIDS or is used for treating other diseases which can be treated, the dosage is reduced on the basis of reaching the same blood concentration, and the potential side effects of the efavirenz are reduced.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained from the drawings without inventive effort.

FIG. 1 shows the results of in vitro dissolution tests of examples 1 to 5 of the present invention;

FIG. 2 is the in vitro dissolution test results of example 6 of the present invention;

FIG. 3 is the in vitro dissolution test results for examples 7 and 8 of the present invention;

FIG. 4 shows the results of comparing the in vivo drug profiles of efavirenz minitablets obtained in examples 7 and 8 of the invention in monkeys.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present application will be described in detail below with reference to specific examples.

On one hand, the embodiment of the application provides an efavirenz micro-tablet, which comprises an inner phase and an outer phase, wherein the mass percent of the inner phase is 87-91.25%, and the mass percent of the outer phase is 8.75-13%; the inner phase is mainly prepared from the following raw materials in percentage by mass: 70 to 80 percent of efavirenz, 4.5 to 10.25 percent of filling agent, 2 to 4 percent of adhesive, 1.5 to 10 percent of disintegrating agent and 1 to 4 percent of surfactant; the external phase is mainly prepared from the following raw materials in percentage by mass: 4.75 to 10.5 percent of filling agent, 0.5 to 1 percent of lubricant and 0.25 to 0.5 percent of thickening agent.

In some embodiments of the invention, in the efavirenz minitablets described above, the filler in the inner phase is cellulose; the binder in the inner phase is povidone k29/32 or hydroxypropyl cellulose.

In some embodiments of the present invention, in the efavirenz mini-tablet described above, the disintegrant in the inner phase is crospovidone XL10, crospovidone INF-10, adirata or sodium carboxymethyl starch.

In some embodiments of the present invention, in the above efavirenz minitablets, the surfactant in the internal phase is sodium lauryl sulfate.

In some embodiments of the present invention, in the above efavirenz minitablets, the filler in the external phase is granulated lactose or microcrystalline cellulose; the lubricant in the external phase is magnesium stearate, and the thickening agent in the external phase is fumed silica.

In some embodiments of the present invention, in the efavirenz micro-tablet, the external phase further comprises 3 to 5% of a disintegrant, wherein the disintegrant comprises crospovidone INF-10, adirata or sodium carboxymethyl starch.

In some embodiments of the present invention, in the efavirenz micro-tablet, the inner phase is mainly prepared from the following raw materials, by mass, 70% of efavirenz, 9% of cellulose, 103% of crospovidone XL, 29/324% of povidone k, and 1% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: granular lactose 9.25%, crospovidone INF-103%, magnesium stearate 0.5% and aerosil 0.25%.

In some embodiments of the present invention, in the efavirenz mini-tablet, the inner phase is mainly prepared from the following raw materials, by mass, 70% of efavirenz, 9% of cellulose, 103% of crospovidone XL, 29/324% of povidone k, and 1% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: granular lactose 9.25%, crospovidone XL103%, magnesium stearate 0.5% and fumed silica 0.25%.

On the other hand, the embodiment of the application provides a preparation method of the efavirenz micro-tablet, which comprises the following steps: pre-dissolving a surfactant and part of a binding agent in water to obtain a granulating solution, sequentially adding efavirenz, a filling agent, a disintegrating agent and the rest of the binding agent in an inner phase into the granulating solution, and uniformly stirring and mixing to obtain a premixed material; granulating the premixed material, sieving and drying to obtain dry granules; and (3) premixing the dry granules and the materials except the thickening agent and the lubricant in the external phase, adding the thickening agent into the mixture, mixing the mixture, adding the lubricant into the mixture, mixing the mixture, and tabletting to obtain the efavirenz micro-tablet.

On the other hand, the embodiment of the application provides the application of the efavirenz micro-tablet in preparing anti-cancer or anti-tumor medicines.

The features and properties of the present application are described in further detail below with reference to examples.

Example 1

The present invention aims to provide efavirenz micro-tablets, which comprise an inner phase and an outer phase (total 100%), wherein the inner phase comprises the following raw materials (mass percent): 70% of efavirenz, 10% of microcrystalline cellulose PH1017.25%, 2% of hydroxypropyl cellulose, 10% of Adeca speed and 2% of sodium dodecyl sulfate; the raw materials for the external phase (mass percent): 7.5% of granulated lactose, 1% of magnesium stearate and 0.25% of fumed silica, wherein the mass ratio of the inner phase to the outer phase is as follows: 91.25:8.75.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

S11, preparing a granulating solution: preparing purified water, sodium lauryl sulfate and a part of a binder (hydroxypropyl cellulose); adding sodium dodecyl sulfate, purified water and part of the binder (hydroxypropyl cellulose) into a 250mL beaker, and stirring by a magnetic stirrer until the mixture is dissolved to obtain a granulation solution;

s12, premixing: sequentially adding micro-powder efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrating agent (namely Adesmi) and an adhesive (namely hydroxypropyl cellulose) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 8min, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm, so as to obtain a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank of the step S12, stirring and shearing for 3-8 min, fully mixing the premixed material and the granulating solution to obtain soft granules, wherein the stirring speed is 450rpm, the shearing speed is 300rpm, and the wetting rate of the soft granules prepared in the process is 79%;

s14, granulating: granulating the soft material obtained in the step S13 in a granulator, wherein the stirring time is 16min, the stirring speed is 450rpm, and the cutting speed is 300rpm;

s15, drying: the pre-drying loss-in-weight (LOD) proportion of the granules obtained in S14 is 43.58%, the granules sieved in S14 are dried in a fluidized bed dryer, the airflow rate level is 2-3/10, the air inlet temperature is 60 ℃, the drying time is 40min, the loss-in-weight (LOD) is 2.06%, and then the granules pass through a 1250-micron screen, so that the dried granules are obtained.

S2, mixing and stirring

S21: sequentially adding S15 obtained particles into a material tank of a mixer (TURBULA), then adding the filler (namely the particle lactose) in the outer phase, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min;

s22: after being screened by a 0.8mm sieve, fumed silica (Aerosil) is introduced into a material tank and is stirred and mixed with the materials in S21, wherein the stirring speed is 22rpm, and the stirring time is 3min;

s23: and (3) passing the magnesium stearate through a 0.8mm screen, introducing the magnesium stearate into a material tank, and uniformly stirring the magnesium stearate and the material in the S22 at the stirring speed of 22rpm for 1min.

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of punching dies, namely 20 punching dies can be pressed after one circle of rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turnplate is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 10-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; friability 0.06-0.57%.

The dissolution rate of the prepared efavirenz micro-tablet is measured, and the result is shown in figure 1, wherein the dissolution rate can reach 70 to 80 percent in 20min and about 90 percent in 40 min.

Example 2

The present embodiment aims to provide an efavirenz micro-tablet, which comprises an internal phase and an external phase, wherein the internal phase is mainly prepared from the following raw materials in percentage by mass: 70% of efavirenz, 1016.5% of microcrystalline cellulose PH, 29/324% of povidone k, 105% of crospovidone INF and 2% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: microcrystalline cellulose PH1026.75%, crospovidone INF-105%, magnesium stearate 0.5%, and fumed silica 0.25%, wherein the mass ratio of the internal phase to the external phase is as follows: 87.5:12.5.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

S11, preparing a granulating solution: preparing purified water, sodium lauryl sulfate and part of the binder (povidone k 29/32); adding sodium dodecyl sulfate, purified water and part of the binder (povidone k 29/32) into a 250mL beaker, and stirring by a magnetic stirrer until the sodium dodecyl sulfate, the purified water and the part of the binder are dissolved to obtain a granulating solution;

s12, premixing: sequentially adding micro-powder efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrating agent (namely crospovidone INF-10) and an adhesive (namely povidone k 29/32) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 3min, wherein the stirring speed is 450rpm and the shearing speed is 300rpm, and obtaining a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank of the step S12, stirring and shearing for 3 to 8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 30.20 percent;

s14, granulating: granulating the soft material obtained in the step S13 in a granulator, wherein the stirring time is 5min, the stirring speed is 450rpm, and the cutting speed is 300rpm; sieving with 3150 μm sieve after granulating;

s15, drying: the pre-drying weight Loss (LOD) ratio of the granules obtained in S14 is 18.7%, the granules sieved in S14 are dried in a fluidized bed dryer, the airflow rate level in the drying process is 1, the air inlet temperature is 60 ℃, the drying time is 12min, the LOD is 1.93%, and then the granules pass through a 1250-micron screen to obtain the dried granules.

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixing stirrer (TURBULA), then adding a filler (namely microcrystalline cellulose PH 102) in an outer phase, adding a disintegrant (namely crospovidone INF-10) in the outer phase after the addition is finished, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min;

s22, after being screened by a 0.8mm sieve, fumed silica (Aerosil) is introduced into a material tank and is stirred and mixed with the materials in the S21, wherein the stirring speed is 22rpm, and the stirring time is 3min;

and S23, passing the magnesium stearate through a 0.8mm screen, introducing the magnesium stearate into a material tank, and uniformly stirring the magnesium stearate and the material in the S22 at a stirring speed of 22rpm for 1min.

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of dies, namely 20 dies can be pressed after one rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turnplate is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 10-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; the friability is 0.06-0.57%.

The results of the dissolution rate test of the prepared efavirenz micro-tablets are shown in figure 1, wherein the dissolution rate can reach more than 70% in 20min and more than 80% in 40 min.

Example 3

The present embodiment aims to provide an efavirenz micro-tablet, which comprises an internal phase and an external phase, wherein the internal phase is mainly prepared from the following raw materials in percentage by mass: 70% of efavirenz, 1019.25% of microcrystalline cellulose PH, 29/324% of povidone k, 102% of crospovidone INF and 4% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: microcrystalline cellulose PH1029.5%, magnesium stearate 1% and aerosil 0.25%, the mass ratio of the inner phase to the outer phase is: 89.25:10.75.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

s12, premixing: sequentially adding micronized efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrant (namely crospovidone INF-10) and an adhesive (namely povidone k 29/32) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 3min, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm, so as to obtain a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank of the step S12, stirring and shearing for 3 to 8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 30.2 percent;

s15, drying: the loss-before-drying (LOD) proportion of the particles obtained in the step S14 is 17.74%, the particles sieved in the step S14 are dried in a fluidized bed dryer, the airflow rate level is 1-2/10 in the drying process, and the air inlet temperature is 60 ℃; drying for 12min; loss On Drying (LOD) was 2.21%, and then passed through a 1250 μm sieve to obtain dry granules.

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixing stirrer (TURBULA), then adding a filler (namely microcrystalline cellulose PH 102) in an outer phase, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min;

s22, guiding fumed silica (Aerosil) into a material tank after passing through a 0.8mm screen mesh, and stirring and mixing the fumed silica and the material in the S21 at a stirring speed of 22rpm for 3min;

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of dies, namely 20 dies can be pressed after one rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turntable is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 10-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; friability 0.06-0.57%.

The dissolution rate of the prepared efavirenz micro-tablet is measured, and the result is shown in figure 1, wherein the dissolution rate can basically reach 70% in 20min and can basically reach about 80% in 40 min.

Example 4

The present embodiment aims to provide an efavirenz micro-tablet, which comprises an internal phase and an external phase, wherein the internal phase is mainly prepared from the following raw materials in percentage by mass: 70% of efavirenz, 10.25% of microcrystalline cellulose PH10110, 29/324% of povidone k, 1.5% of sodium carboxymethyl starch and 2% of sodium dodecyl sulfate;

the external phase is mainly prepared from the following raw materials in percentage by mass: 10.5% of granular lactose, 1% of magnesium stearate, 0.5% of sodium carboxymethyl starch and 0.25% of fumed silica, wherein the mass ratio of the inner phase to the outer phase is as follows: 87.75:12.25.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

s12, premixing: sequentially adding micro-powder efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrating agent (namely sodium carboxymethyl starch) and an adhesive (namely povidone k 29/32) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 3min, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm, so as to obtain a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank in the step S12, stirring and shearing for 3-8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 30.3 percent;

s14, granulating: granulating the soft material obtained in the step S13 in a granulator, wherein the stirring time is 5min, the stirring speed is 450rpm, and the chopping speed is 300rpm; sieving with 3150 μm sieve after granulating;

s15, drying: the loss before drying (LOD) proportion of the particles obtained in the step S14 is 18.96%, the particles sieved in the step S14 are dried in a fluidized bed dryer, the airflow rate level is 1-2/10 in the drying process, and the air inlet temperature is 60 ℃; drying for 12min; loss On Drying (LOD) was 1.7%, and then passed through a 1250 μm sieve to obtain dry granules.

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixer (TURBULA), then adding a filler (namely particle lactose) in an outer phase, and stirring until the mixture is uniformly mixed at a stirring speed of 22rpm for 3min;

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of dies, namely 20 dies can be pressed after one rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turntable is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 15-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; the friability is 0.06-0.57%.

The dissolution rate of the prepared efavirenz micro-tablet is determined, and the result is shown in figure 1, wherein the dissolution rate of the efavirenz micro-tablet can basically reach 60% within 20min, and the dissolution rate of the efavirenz micro-tablet can basically reach about 70% within 40 min.

Example 5

The present embodiment aims to provide an efavirenz micro-tablet, which comprises an internal phase and an external phase, wherein the internal phase is mainly prepared from the following raw materials in percentage by mass: 70% of efavirenz, 1017.5% of microcrystalline cellulose PH, 29/324% of povidone k, 3% of Adeca speed and 4% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: 7.75% of granulated lactose, 3% of adix, 0.5% of magnesium stearate and 0.25% of aerosil, the mass ratio of the internal phase to the external phase being: 88.5:11.5.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

s12, premixing: sequentially adding micronized efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrating agent (namely Adesmi) and an adhesive (namely povidone k 29/32) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 4min, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm, so as to obtain a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank of the step S12, stirring and shearing for 3 to 8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 46.6 percent;

s14, granulating: granulating the soft material obtained in the step S13 in a granulator, wherein the stirring time is 7min, the stirring speed is 450rpm, and the chopping speed is 300rpm; sieving with 3150 μm sieve after granulating;

s15, drying: the loss-before-drying (LOD) proportion of the particles obtained in the step S14 is 25.93%, the particles sieved in the step S14 are dried in a fluidized bed dryer, the airflow rate level is 5-6/10 in the drying process, and the air inlet temperature is 60 ℃; drying for 12min; loss On Drying (LOD) was 1.48%, and then passed through a 1250 μm sieve to obtain dry granules.

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixing stirrer (TURBULA), then adding a filler (particle lactose) in the outer phase, adding a disintegrant (AiDI speed) in the outer phase after the addition is finished, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min;

S3, tabletting

The dissolution rate of the prepared efavirenz micro-tablet is measured, and the result is shown in figure 1, and the dissolution rate can reach about 70 percent within 40 min.

Example 6

The present embodiment aims to provide an efavirenz micro-tablet, which comprises an internal phase and an external phase (total 100%), wherein the internal phase comprises the following raw materials (by mass): efavirenz 80%, microcrystalline cellulose PH1014.5%, povidone k29/322%, sodium carboxymethyl starch 6% and sodium dodecyl sulfate 2%; the raw materials (mass percent) used in the external phase are as follows: microcrystalline cellulose PH1024.75%, magnesium stearate 0.5% and aerosil 0.25%, the mass ratio of inner phase and outer phase is: 94.5:5.5.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank in the step S12, stirring and shearing for 3-8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 40 percent;

s15, drying: the loss before drying (LOD) proportion of the particles obtained in the step S14 is 31.41%, the particles sieved in the step S14 are dried in a fluidized bed dryer, the airflow rate level is 3-4/10 in the drying process, and the air inlet temperature is 60 ℃; drying for 18min; loss On Drying (LOD) was 1.09%, and then passed through a 1250 μm sieve to obtain dry granules.

S2, mixing and stirring

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of punching dies, namely 20 punching dies can be pressed after one circle of rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turntable is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 10-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; the friability is 0.06-0.57%.

The dissolution rate of the prepared efavirenz micro-tablet is determined, and the result is shown in figure 2, wherein the dissolution rate can reach about 85% in 20min and about 90% in 40 min.

Effect example 1

In examples 1 to 6, the dissolution test conditions in vitro of the faviren mini-tablets provided in examples 1 to 6 of the present invention were measured by the paddle method. The conditions for determining in vitro dissolution were as follows: defined solvent (dissolution medium): simulated gastric fluid +0.2% Sodium Lauryl Sulfate (SLS); dissolution rate measurement temperature: at 37 ℃; rotating speed of a stirring paddle: 50rpm; volume of solvent: 500mL;3 tablets/group, parallel test group n =3, statistical mean values were plotted for drug dissolution curves. Sampling time points (min) include 5, 10, 20, 30, 40, 60, 120, 240. All dissolution tests are completed by adopting a SOTAX DT3 dissolution tester.

The test results are shown in fig. 1:

judging from the disintegration time (20 min disintegration speed): efavirenz 70% is better than 80%, adhesive 2% is better than 4%, adhesive type PVP is better than HPC, SLS proportion is better than 4%, external phase filler cellulose is better than granular lactose, magnesium stearate dosage is better than 1% at 0.5%, disintegrant is better than 2% and 6%, and the proportion of internal phase and external phase is 75/25, preferably 50/50 and 100/0.

Judging from the disintegration time (disintegration ratio within 20 min): the use of 70% or 80% of efavirenz has little effect on this, 4% of binder is better than 2%, PVP of binder type is better than HPC, the SLS ratio is better than 4%, cellulose of the filler of the external phase is better than lactose of granules, the use of 0.5% or 1% of magnesium stearate has little effect on this, 10% of disintegrant is better than 2% and 6%, the ratio of internal phase to external phase is 100/0 optimal and better than both types 50/50 and 75/25.

Judging from the disintegration time (disintegration ratio within 60 min): the use of 70% or 80% of efavirenz has little effect on this, 4% of the binder is better than 2%, the binder type polyvinylpyrrolidone (PVP) is better than Hydroxypropylcellulose (HPC), the SLS proportion is better than 4%, both the external phase filler cellulose and the granulated lactose can be used, the use of 0.5% or 1% of magnesium stearate has little effect on this, 10% of disintegrant is better than 2% and 6%, the ratio of internal phase to external phase is 100/0 optimal and better than both types 50/50 and 75/25.

As for the disintegrant, although the foregoing examples used various disintegrants, in consideration of practical production costs and processes, the use of crospovidone XL10 and crospovidone INF-10 was finally selected for subsequent studies.

In combination with the above test results, example 7 and example 8 were designed. Since the disintegrant has a large influence in drug dissolution and absorption: the particle size of the particles is small, the uniformity and the dissolution rate of the tablet medicine can be improved, and the particle is suitable for low-dose or water-insoluble medicines; and is favorable for improving the taste of the medicine. Therefore, in examples 7 and 8, a disintegrant with a smaller particle size is used, wherein the particle size of crospovidone XL10 is 30 μm, and the particle size of crospovidone INF-10 is 10 μm, and the specific materials and preparation method are as follows.

Example 7

The inner phase of the efavirenz micro-tablet is mainly prepared from the following raw materials in percentage by mass, namely 70% of efavirenz, 9% of cellulose, 103% of crospovidone XL, 29/324% of povidone k and 1% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: 9.25% of granulated lactose, 9.25% of crospovidone INF-103%, 0.5% of magnesium stearate and 0.25% of fumed silica, wherein the mass ratio of the internal phase to the external phase is as follows: 87:13.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

s12, premixing: sequentially adding micronized efavirenz, a filler (namely microcrystalline cellulose PH 101), a disintegrant (namely crospovidone XL 10) and a binder (namely povidone k 29/32) into the granulating solution, sequentially introducing into a 6LHSM (high speed cutting) material tank of a granulator, stirring and chopping for 3min, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm, so as to obtain a premixed material;

s13, preparing soft granules: introducing the granulating solution prepared in the step S11 into the material tank in the step S12, stirring and shearing for 3-8min, fully mixing the premixed material and the granulating solution to prepare soft granules, wherein the stirring speed is 450rpm, and the shearing speed is 300rpm; the wetting rate of the soft granules prepared in the process is 30-79%;

s14, granulating: granulating the soft material obtained in the step S13 in a granulator, wherein the stirring time is 5-8min, the stirring speed is 450rpm, and the cutting speed is 300rpm; sieving with 3150 μm sieve after granulating;

s15, drying: the loss before drying (LOD) proportion of the particles obtained in the S14 is 17.74-25.96%, the particles sieved in the S14 are dried in a fluidized bed dryer, the airflow rate level is 1-2/10,5-6/10,7-8/10 and the air inlet temperature is 60 ℃ in the drying process; drying for 12-15min; loss On Drying (LOD) of 1.30-2.84%, followed by passing through a 1250 μm sieve to obtain dry granules.

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixing stirrer (TURBULA), then adding a filler (microcrystalline cellulose PH 102) in the outer phase, adding a disintegrant (namely crospovidone INF-10) in the outer phase after the addition is finished, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min;

S3, tabletting

In the tabletting step, an SVIAC RP2080 rotary tablet press is used; the tablet press is of a double-pressure structure and is provided with two sets of feeding devices and two sets of rotating discs; each turntable can be provided with 10 pairs of dies, namely 20 dies can be pressed after one rotation; the target hardness of the compressed tablet is set to 15N to 20N; the operating parameters were set as follows: the die hole size is D3R17; the speed of the tabletting turntable is 5-6rpm; the material filling speed is 90rpm; the compressed tablets were white round tablets; the quality uniformity of the tablet is 22.5-26.6mg; the hardness of the tablet is 10-35N; the thickness is 3.39-3.77mm; the diameter is 3.05-3.11mm; the friability is 0.06-0.57%.

The dissolution rate of the prepared efavirenz micro-tablet is measured, and the result is shown in figure 3, wherein the dissolution rate can basically reach 80% in 20min and can basically reach about 90% in 40 min.

Example 8

The inner phase of the efavirenz micro-tablet is mainly prepared from the following raw materials in percentage by mass, namely 70% of efavirenz, 9% of cellulose, 103% of crospovidone XL, 29/324% of povidone k and 1% of sodium dodecyl sulfate; the external phase is mainly prepared from the following raw materials in percentage by mass: 9.25% of granular lactose, 103% of crospovidone XL, 0.5% of magnesium stearate and 0.25% of fumed silica, wherein the mass ratio of the inner phase to the outer phase is as follows: 87:13.

The efavirenz micro-tablet is mainly prepared by the following steps:

s1, granulating

S11, preparing a granulating solution: preparing purified water, sodium lauryl sulfate and part of the binder (povidone k 29/32); adding sodium dodecyl sulfate, purified water and part of the binder (povidone k 29/32) into a 250mL beaker, and stirring with a magnetic stirrer until the mixture is dissolved to obtain a granulation solution;

S2, mixing and stirring

S21, sequentially adding the particles obtained in the step S15 into a material tank of a mixing stirrer (TURBULA), then adding a filler (microcrystalline cellulose PH 102) in the outer phase, adding a disintegrant (namely crospovidone INF-10) in the outer phase after the addition is finished, and stirring until the mixture is uniformly mixed, wherein the stirring speed is 22rpm, and the stirring time is 3min.

S22, guiding the fumed silica (Aerosil) into a material tank after passing through a 0.8mm screen mesh, and stirring and mixing the fumed silica and the materials in the S21 at a stirring speed of 22rpm for 3min.

S3, tabletting

The dissolution rate of the prepared efavirenz micro-tablet is measured, and the result is shown in figure 3, wherein the dissolution rate can reach 70% in 20min and about 75% in 40 min.

The granular lactose used in examples 1 to 8 was Tablettose 80 (German Meijile (Meggle)), in which fumed silica was used in an amount of 0.25%, and the actual production was increased to 0.5% as appropriate.

Effect example 2

1. Dissolution test

In examples 7 and 8, effect example 1 was referred to for the in vitro dissolution measurement method. Results as shown in table 1, table 2 and fig. 3, the dissolution rate and the dissolution percentage of the efavirenz minitablets provided in example 7 are superior to those of the efavirenz minitablets provided in example 8. Therefore, the use of different disintegrants in the inner phase and the outer phase is beneficial to improving the dissolution performance of efavirenz, and meanwhile, the disintegrant with small particle size can be disintegrated into smaller particles, so that the bioavailability of the medicine is improved.

Table 1 dissolution results for efavirenz microtablets provided in example 7

Table 2 dissolution results for efavirenz minitablets provided in example 8

2. Plasma drug concentration determination

2.1 Sample preparation

Monkeys were selected as animal models and the dose was set at 100 mg/monkey. Plasma sample sampling time points were set as: before administration, 0.25,0.5,1,2,3,4,6,8, 24, 32, 48, 56, 72 hours after administration. Plasma drug concentrations were determined using high performance liquid chromatography-mass spectrometry (LC-MS/MS). The lower limit of detection of the blood concentration of efavirenz is 1.00ng/ml.

50 μ L of plasma samples were mixed with 300 μ L acetonitrile containing an internal standard (25 ng/mL tolbutamide). The mixture was centrifuged at 4000rpm for 15min. 50 μ L of the supernatant was collected, diluted with 50 μ L of purified water and used for liquid chromatography-mass spectrometry LC-MS/MS analysis.

2.2 LC-MS/MS liquid chromatography-mass spectrometry

The separation step of liquid chromatography was carried out at room temperature using a Kinetex 2.6. Mu.mC 18100A column (30X 3.0 mm) and the flow rate was set to 1.0mL/min. Mobile phase a was an aqueous solution containing 0.1% formic acid and mobile phase B was an acetonitrile solution containing 0.1% formic acid. Linear gradient: 25% B by keeping for 0.3min, B from 25% to 90%, by keeping for more than 0.7min,90% B by washing for 0.5min, finally rebalancing using 25% B. The total run time was 2min. The plasma volume for loading injection was 2/5. Mu.L. Mass spectrometers were selected (API-4000, applied biosystems/MDSSCIEXInstructions, foster City, calif.). The mass spectrometer selects the negative ion scanning Multiple Reaction Monitoring (MRM) mode. The parent-child ion pairs (MRMtransitions, each pair of transitions being specific and representing a particular molecule) used to characterize efavirenz with the internal standard (tolbutamide) were 314.02/68.90 and 268.80/169.80, respectively. The collision energy CE of efavirenz with the internal standard (tolbutamide) was 30volts and 22volts, respectively.

2.3 data analysis

For the experimental group administered at a dose of 100 mg/monkey: standard samples and Quality Control (QC) samples were prepared using blank monkey plasma. The numeric area of the standard curve is 1.00-2000ng/mL, the lower limit of metering (LOQ) is 1.00ng/mL, and the concentration of the quality control sample is set to be 2.00ng/mL,500ng/mL and 1600ng/mL. The range of the standard curve of the plasma repeated test is 20.0-10000ng/mL, the lower limit of metering (LOQ) is 20.0ng/mL, and the concentration of the quality control sample is set to be 50.0ng/mL,2000ng/mL and 8000ng/mL.

The data acceptance criteria (acceptance criteria) are as follows:

(1) Calculating standard curve values (6/8 concentration data) and nominal concentrations not deviating more than 20% from each other based on the ratio of analyte to internal standard peak areas using 1/x2 weighted linear regression analysis;

(2) Rsq (goodness of fit) must be greater than 0.98;

(3) At least two-thirds of the quality control sample data values are within ± 20% of the nominal concentration.

Statistical results as shown in table 3 and fig. 4, it can be seen that the efavirenz minitablets provided in examples 7 and 8 both reach their peak within 5min and can be used for clinical trials or dose-adjustment optimization of patients.

Table 3 statistical comparison of pharmacokinetic parameters in monkeys for efavirenz minitablets provided in example 7 and example 8 (n = 4/group)

In conclusion, the efavirenz micro-tablet provided by the invention optimizes the conventional 600 mg/tablet large-dose efavirenz into a 22.5-26.6 mg/tablet micro-tablet dosage form, and the content of efavirenz in the micro-tablet is 70%, so that the effective content of efavirenz can be ensured, and the adjustment of the dose in clinic or research is facilitated. By adding specific auxiliary materials and utilizing a specific preparation method, the prepared efavirenz micro-tablet has high dissolution rate in unit time, can reach a peak within 6.5 to 7 hours after being taken, can keep the same or better bioavailability as the original efavirenz, can flexibly adjust the administration dosage in the clinical research process, reduces the difference between subjects with blood concentration after administration, and provides certain assistance for promoting clinical research. In addition, in the actual use process, the dose of the efavirenz can be flexibly adjusted whether the efavirenz is used for treating prostate cancer or AIDS or other diseases which can be treated, such as other cancers or tumors, and the like, so that the bioavailability of patients (including general users and clinical research volunteers and the like) is improved, the dose is reduced on the basis of reaching the same blood concentration, and the potential side effects of the efavirenz are reduced. In addition, for patients who have disorder when taking large-tablet efavirenz, the micro-tablet efavirenz provided by the invention can be taken to relieve the disorder and ensure the treatment effect.

The embodiments described above are some, but not all embodiments of the present application. The detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but is merely representative of selected embodiments of the application. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.

Claims

1. Efavirenz microtablets characterized by comprising an internal phase and an external phase,

the inner phase is prepared from the following raw materials in percentage by mass: 70% of efavirenz, 9% of a filling agent, 3% of a disintegrating agent, 4% of a binding agent and 1% of a surfactant; wherein the filler in the inner phase is microcrystalline cellulose PH101, the disintegrant is crospovidone XL10, the binder is povidone k29/32, and the surfactant is sodium dodecyl sulfate;

the external phase is prepared from the following raw materials in percentage by mass: 9.25 percent of filling agent, 3 percent of disintegrating agent, 0.5 percent of lubricating agent and 0.25 percent of thickening agent; wherein the filler in the outer phase is granular lactose, the disintegrant is crospovidone INF-10, the lubricant is magnesium stearate, and the thickener is fumed silica;

the preparation method of the efavirenz micro-tablet comprises the following steps: pre-dissolving a surfactant and part of a binding agent in water to obtain a granulating solution, sequentially adding efavirenz, a filling agent, a disintegrating agent and the rest of the binding agent in an inner phase into the granulating solution, and uniformly stirring and mixing to obtain a premixed material; granulating the premixed material, sieving and drying to obtain dry particles; premixing the dry granules and the materials except the thickening agent and the lubricant in the external phase, adding the thickening agent into the mixture, mixing the mixture, adding the lubricant into the mixture, mixing the mixture, and tabletting to obtain the efavirenz micro-tablet; the mass of the efavirenz micro-tablet is 22.5-26.6mg.

2. A process for preparing efavirenz microtablets as claimed in claim 1, comprising the steps of: pre-dissolving a surfactant and part of a binding agent in water to obtain a granulating solution, sequentially adding efavirenz, a filling agent, a disintegrating agent and the rest of the binding agent in an inner phase into the granulating solution, and uniformly stirring and mixing to obtain a premixed material; granulating the premixed material, sieving and drying to obtain dry particles; premixing the dry particles and the materials except the thickening agent and the lubricant in the external phase, adding the thickening agent into the dry particles and the materials except the thickening agent and the lubricant, then adding the lubricant into the dry particles and the materials and mixing the materials, and tabletting to obtain the efavirenz micro-tablet.

3. Use of efavirenz minitablets according to claim 1 for the preparation of an antitumor medicament.